2-(Methylthio)naphtho[1,3-bc]pyran-3(2H)-one

ABSTRACT

The invention relates to novel compounds having the formulas I and III: ##STR1## wherein, in formula I, X is --O-- or --N--COR wherein R is lower alkyl or aryl, and Z is ##STR2## WHEREIN R&#39; is hydrogen, halogen or alkoxy. the compounds of this invention are prepared by a novel process which involves the cyclization of the corresponding aryl(methylsulfinyl)methyl ketones. The compounds of this invention having formulas I and III are useful in the treatment of hyperacidity and for alleviating allergic manifestations.

This is a division of Ser. No. 571,890 filed Apr. 25, 1975, now U.S.Pat. No. 4,012,442 which is a division of Ser. No. 464,706, filed April26, 1974, now U.S. Pat. No. 3,920,699.

DESCRIPTION OF THE INVENTION The present invention relates to novelsubstituted-2-(methylthio)-3(2H)-benzofuranones and novelsubstituted-2-(methylthio)-3-indolinones having the formula I: ##STR3##wherein X is -- O-- or --N--COR wherein R is lower alkyl or aryl, and Zis ##STR4## WHEREIN R' is hydrogen, halogen or alkoxy; and to novel2-(methylthio)naphtho[ 1,8-bc]pyran-3-(2H)-one having the formula III:##STR5##

This invention also includes within its scope a novel process forpreparing the above compounds as well as certain novel intermediatesused in their preparation.

The novel compounds of the invention having formula I, as defined above,are prepared by cyclizing the corresponding aryl(methylsulfinyl)methylketone having the formula II: ##STR6## wherein X is -- 0-- or --N--CORwherein R is lower alkyl or aryl, and Z is ##STR7## WHEREIN R' ishydrogen, halogen or alkoxy.

This cyclization reaction involves refluxing the keto sulfoxide startingmaterial II with an equivalent of trifluoroacetic acid in a suitablesolvent, such as benzene, toluene or the like, for one to two hours.

The starting materials having the formula II as described above whereinX is oxygen are prepared as described in U.S. Pat. No. 3,801,644,patented Apr. 2, 1974: dimethyl sulfoxide is reacted with sodium hydridein an inert solvent to which is added an appropriately substitutedortho-hydroxy aromatic ester; the temperature is maintained at not morethan 50° C. and the reaction product is precipitated by the addition ofa nonpolar solvent. Substitutedo-hydroxy-ω-(methylsulfinyl)acetophenones or substitutedo-hydroxy-ω-(methylsulfinyl)acetonaphthones used as starting materialsfor certain of the compounds of this invention are obtained by thismethod. For example, 2'-hydroxy-2-(methylsulfinyl)acetophenone;2'-hydroxy-3'-methoxy-2-(methylsulfinyl)acetophenone;5'-chloro-2'-hydroxy-2-(methylsulfinyl)acetophenone; 3'-hydroxy-2-(methylsulfinyl)-2'-acetonaphthone may be prepared by this method.

Starting materials having the formula II wherein X is --N-- COR, with Rrepresenting lower alkyl or aryl, are prepared as described in M. vonStrandtmann et al, Journal Organic Chemistry, 36: 1742-1744 (1971) bythe addition of sodium methylsulfinylmethide to the appropriately3-substituted-2,4-benzoxazin-1-one, to obtain such compounds as2'[(methylsulfinyl)acetyl]benzanilide;2'[(methylsulfinyl)acetyl]naphthylbenzamide;2'[(methylsulfinyl)acetyl]-loweralkyl-benzamide, and the like.

Similarly, novel compounds of the invention having the formula III:##STR8## are prepared by refluxing a compound of the formula IV:##STR9## dissolved in a suitable solvent, with an equivalent oftrifluoroacetic acid for one to two hours. Starting material IV,(8'hydroxy-2-(methylsulfinyl)-1'acetonaphthone) is also novel and isprepared by the addition of sodium methylsulfinylmethide to2H-naphtho[1,8-bc]furan-2-one.

Among the preferred compounds of the invention having formula I theremay be mentioned those wherein R represents 1 to 3 carbon lower alkyl orphenyl; and R' is hydrogen, chloro or 1 to 3 carbon lower alkoxy.

In all of the structures in the specification and in the claims the term"alkyl" and the alkyl portion of "alkoxy" is meant to include straightand branched chain alkyl radicals containing from 1 to 7 carbon atoms,for example, methyl, ethyl, propyl, isopropyl, butyl, n-hexyl and thelike. The term "halogen" encompasses fluorine, bromine, chlorine andiodine. The term "aryl" denotes unsaturated cyclic hydrocarbon radicalsderived from benzene, such as phenyl or naphthyl.

The compounds of this invention are active orally or when injected, forthe prevention of allergic and asthmatic reactions in mammals such ascats, dogs, rats, guinea pigs and the like, at dosage levels of 25 to150 mg/kg of body weight. This,7-methoxy-2-(methylthio)-3(2H)-benzofuranone shows a 34% inhibition ofthe allergic response at 25 mg/kg when tested in the passive cutaneousanaphalaxis (PCA) screen, which is a modification of proceduresdescribed by I. Mota, Life Sciences, 7, 465 (1963) and Z. Ovary and O.Bier, Proc. Soc. Exptl. Biol. Med., 81, 585 (1952). Consequently, thecompounds I and III of this invention are useful in the treatment ofasthma, hay fever and other allergic conditions.

In addition to the above-mentioned utility, the compounds of thisinvention having formulas I and III also inhibit hyperacidity inaforementioned mammals when administered orally or by injection atdosages of 10 to 100 mg/kg of body weight. For example, when2-(methylthio)-3(2H)-benzofuranone is tested according to the proceduredescribed by H. Shay, et al., Gastroenterology, 5, 43 (1945), in thepylorus ligated rat, at a dose of 20 mg/kg of body weight, injectedintraperitoneally, it caused a reduction of 49.6% in volume of gastricacid and a 28% reduction in the ion acid compared to controls. Thus,compounds having the formulas I and III are useful in the treatment ofgastric ulcers.

In order to use the compounds of the invention having formulas I and IIIas described above, they may be formulated with standard pharmaceuticalcarriers such as lactose, mannitol, dicalcium phosphate and the like,into dosage forms such as tablets, capsules and the like. They can alsobe combined with parenterally acceptable vehicles such as polyethyleneglycol, sesame oil, peanut oil or the like, for injectable dosage forms.

To further illustrate the practice of this invention the followingexamples are included.

EXAMPLE I ##STR10## 2-(Methylthio)-3(2H)-benzofuranone

2-Hydroxy-1-[(methylsulfinyl)acetyl] benzene (1.5 g 0.0075m) andtrifluoroacetic acid (1.5 g) are refluxed in benzene (25 ml) for onehour under nitrogen. The solvent is removed under reduced pressure togive a pale yellow oil which crystallizes on standing. Recrystallizationfrom ethanol gave white crystals, (0.611 g 45%), m.p. 81°-82° C.

Anal. Calcd. for C₉ H₈ O₂ S: C, 59.98; H, 4.47; S, 17.79. Found: C,60.12; H, 4.49; S, 17.78.

EXAMPLE II ##STR11## 7-Methoxy-2-(methylthio)-3(2H)-benzofuranone

Prepared by the general method described in Example I, starting with2-hydroxy-3-methoxy-1-[(methylsulfinyl)acetyl]benzene. Recrystallizationfrom absolute ethanol gives white crystals, (89 g 65%), m.p. 103°-105°C.

Anal. Calcd. for C₁₀ H₁₀ O₃ S: C, 57.13; H, 4.79; S, 15.25. Found: C,57.28; H, 4.97; S, 15.36.

EXAMPLE III ##STR12## 2-(Methylthio)-naphtho[2,3-b]furan-3(2H)-one

Prepared by the general procedure described in Example I, starting with3-hydroxy-2-[(methylsulfinyl)acetyl]naphthalene. Recrystallization fromethanol gives yellow crystals, (1.5 g 81%), m.p. 118°-120° C.

Anal. Calcd. for C₁₃ H₁₀ SO₂ : C, 67.80; H, 4.38; S, 13.92. Found: C,67.64; H, 4.46; S, 13.94.

EXAMPLE IV ##STR13## 2-(Methylthio)naphho[1,8-bc]pyran-3(2H)-one

Prepared by the general procedure described in Example I, starting with8-hydroxy-1-[(methylsulfinyl)acetyl]naphthalene (1 g). Recrystallizationfrom ethanol gives yellow-brown crystals, (600 mg 64%), m.p. 89°-91° C.

Anal. Calcd. for C₁₃ H₁₀ O₂ S: C, 67.80; H, 4.38; S, 13.92. Found: C,67.60; H, 4.49; S, 13.89.

EXAMPLE V ##STR14## 5-Chloro-2-(methylthio)-3(2H)-benzofuranone

5-Chloro-2-hydroxy-1-[(methylsulfinyl)acetyl]benzene (6.0 g) andtrifluoroacetic acid (6 g) are refluxed in benzene (50 ml) for one hourunder nitrogen. The solvent is removed under reduced pressure to give ayellow oil, which crystallizes on standing. Recrystallization fromethanol gives white crystals. (3.0 g 54%) m.p. 76°-78° C.

Anal. Calcd. for C₉ H₇ ClO₂ S: C, 50.36; H, 3.29; Cl, 16.51; S, 14.94.Found: C, 50.18; H, 3.22; Cl, 16.73; S, 14.70.

EXAMPLE VI ##STR15## 1-Benzoyl-2-(methylthio)-3-indolinone

2'-[(methylsulfinyl)-acetyl]benzanilide (7 g) is refluxed in benzenecontaining 1 equivalent of trifluoroacetic acid for one hour. Thesolvents are removed under reduced pressure to give an oil whichcrystallizes on standing. Recrystallization from ethyl acetate gives1-benzoyl-2-(methylthio-3-indolinone (4.5 g 67%) m.p. 126°-128° C.

Anal. Calcd. for C₁₆ H₁₃ NO₂ S: C, 67.82; H, 4.62; N, 4.94; S, 11.32.Found: C, 67.66; H, 4.70; N, 4.94; S, 11.29.

We claim:
 1. 2-(Methylthio)naphtho[1,8-bc]pyran-3(2H)-one.